Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-κB-regulated gene products

被引:90
作者
Ahn, Kwang Seok
Sethi, Gautam
Chao, Ta-Hsiang
Neuteboom, Saskia T. C.
Chaturvedi, Madan M.
Palladino, Michael A.
Younes, Anas
Aggarwal, Bharat B.
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Expt Therapeut, Cytokine Res Lab, Houston, TX 77030 USA
[2] Nereus Pharmaceut, San Diego, CA USA
[3] Univ Delhi, Dept Zool, Delhi 110007, India
[4] Univ Texas, MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA
关键词
D O I
10.1182/blood-2007-04-084996
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Salinosporamide A (also called NPI-0052), recently identified from the marine bacterium Salinispora tropica, is a potent inhibitor of 20S proteasome and exhibits therapeutic potential against a wide variety of tumors through a poorly understood mechanism. Here we demonstrate that salinosporamide A potentiated the apoptosis induced by tumor necrosis factor alpha (TNF), bortezomib, and thalidomide, and this correlated with down-regulation of gene products that mediate cell proliferation (cyclin D1, cyclooxygenase-2 [COX-2], and c-Myc), cell survival (Bcl-2, Bcl-xL, cFLIP, TRAF1, IAP1, IAP2, and survivin), invasion (matrix metalloproteinase-9 [MMP-9] and ICAM-1), and angiogenesis (vascular endothelial growth factor [VEGF]). Salinosporamide A also suppressed TNF-induced tumor cell invasion and receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis. We also found that it suppressed both constitutive and inducible NF-kappa B activation. Compared with bortezomib, MG-132, N-acetyl-leucyl-leucyl-norleucinal (ALLN), and lactacystin, salinosporamicle A was found to be the most potent suppressor of NF-kappa B activation. Further studies showed that salinosporamide A inhibited TNF-induced inhibitory subunit of NF-kappa B alpha (I kappa B alpha) degradation, nuclear translocation of p65, and NF-kappa B-dependent reporter gene expression but had no effect on l kappa B alpha kinase activation, I kappa B alpha phosphorylation, or I kappa B alpha ubiquitination. Thus, overall, our results indicate that salinosporamicle A enhances apoptosis, suppresses osteoclastogenesis, and inhibits invasion through suppression of the NF-kappa B pathway.
引用
收藏
页码:2286 / 2295
页数:10
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